PTPN6

Tyrosine-protein phosphatase non-receptor type 6, also known as Src homology region 2 domain-containing phosphatase-1 (SHP-1), is an enzyme that in humans is encoded by the PTPN6 gene.[5]

PTPN6
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1FPR, 1GWZ, 1X6C, 2B3O, 2RMX, 2YU7, 3PS5, 4GRY, 4GRZ, 4GS0, 4HJP, 4HJQ
Identifiers
Aliases	PTPN6, HCP, HCPH, HPTP1C, PTP-1C, SH-PTP1, SHP-1, SHP-1L, SHP1, protein tyrosine phosphatase, non-receptor type 6, protein tyrosine phosphatase non-receptor type 6
External IDs	OMIM: 176883 MGI: 96055 HomoloGene: 56589 GeneCards: PTPN6
Gene location (Human) Chr. Chromosome 12 (human)[1] Band 12p13.31 Start 6,946,468 bp[1] End 6,961,316 bp[1]
Gene location (Mouse) Chr. Chromosome 6 (mouse)[2] Band 6 F2|6 59.17 cM Start 124,720,707 bp[2] End 124,738,714 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • phosphoprotein phosphatase activity • SH3 domain binding • phosphatase activity • phosphotyrosine residue binding • SH2 domain binding • GO:0001948 protein binding • transmembrane receptor protein tyrosine phosphatase activity • hydrolase activity • protein kinase binding • cell adhesion molecule binding • protein tyrosine phosphatase activity • phosphorylation-dependent protein binding Cellular component • cytoplasm • cytosol • membrane • intercellular junction • alpha-beta T cell receptor complex • nucleolus • extracellular exosome • cell nucleus • extracellular region • specific granule lumen • tertiary granule lumen • nucleoplasm • macromolecular complex Biological process • B cell receptor signaling pathway • megakaryocyte development • G-protein coupled receptor signaling pathway • cell differentiation • GO:0007243 intracellular signal transduction • regulation of release of sequestered calcium ion into cytosol • abortive mitotic cell cycle • T cell costimulation • protein dephosphorylation • platelet formation • negative regulation of T cell receptor signaling pathway • platelet activation • negative regulation of humoral immune response mediated by circulating immunoglobulin • regulation of G1/S transition of mitotic cell cycle • negative regulation of T cell proliferation • regulation of type I interferon-mediated signaling pathway • negative regulation of peptidyl-tyrosine phosphorylation • negative regulation of MAP kinase activity • hematopoietic progenitor cell differentiation • positive regulation of cell proliferation • negative regulation of MAPK cascade • regulation of ERK1 and ERK2 cascade • negative regulation of B cell receptor signaling pathway • peptidyl-tyrosine phosphorylation • positive regulation of phosphatidylinositol 3-kinase signaling • positive regulation of cell adhesion mediated by integrin • cellular proliferation • platelet aggregation • regulation of B cell differentiation • leukocyte migration • natural killer cell mediated cytotoxicity • negative regulation of cell proliferation • dephosphorylation • apoptotic process • neutrophil degranulation • peptidyl-tyrosine dephosphorylation • cytokine-mediated signaling pathway • negative regulation of interleukin-6 production • negative regulation of tumor necrosis factor production • cellular response to cytokine stimulus Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	5777	15170
Ensembl	ENSG00000111679	ENSMUSG00000004266
UniProt	P29350	P29351
RefSeq (mRNA)	NM_002831 NM_080548 NM_080549	NM_001077705 NM_013545
RefSeq (protein)	NP_002822 NP_536858 NP_536859	NP_001071173 NP_038573
Location (UCSC)	Chr 12: 6.95 – 6.96 Mb	Chr 6: 124.72 – 124.74 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. N-terminal part of this PTP contains two tandem Src homolog (SH2) domains, which act as protein phospho-tyrosine binding domains, and mediate the interaction of this PTP with its substrates. This PTP is expressed primarily in hematopoietic cells, and functions as an important regulator of multiple signaling pathways in hematopoietic cells. This PTP has been shown to interact with, and dephosphorylate a wide spectrum of phospho-proteins involved in hematopoietic cell signaling, (e.g., the LYN-CD22-SHP-1 pathway). Multiple alternatively spliced variants of this gene, which encode distinct isoforms, have been reported.[6]

Expression

SHP-1 gene has two promoters: P-1, active in epithelial cells, and P-2, active in hemopoietic cells. In addition the expression of SHP-1 is low in epithelial cells and high in hemopoietic cells. SHP-1 level in epithelial cells increases and in hematopoetic cells decreases in cancer.[7]

Interactions

PTPN6 has been shown to interact with:

• BCR gene,[8]
• CD117,[9][10]
• CD22,[11][12][13][14][15]
• CD31,[16][17]
• CTNND1,[18]
• EGFR,[19][20]
• EPOR,[21]
• FCRL3,[22]
• Grb2,[23][24][25]
• HOXA10,[26]
• JAK2,[27][28]
• LAIR1,[29][30][31][32][33]
• LILRB2,[34][35]
• LILRB4,[36]
• Lck,[37][38][39]
• LCP2,[40][41]
• PRKCD,[42]
• PTK2B,[23][43]
• ROS1,[44]
• SIRPA,[29][45]
• SYK,[23][46] and
• TYK2.[47]

References

1. GRCh38: Ensembl release 89: ENSG00000111679 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000004266 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Plutzky J, Neel BG, Rosenberg RD, Eddy RL, Byers MG, Jani-Sait S, Shows TB (August 1992). "Chromosomal localization of an SH2-containing tyrosine phosphatase (PTPN6)". Genomics. 13 (3): 869–72. doi:10.1016/0888-7543(92)90172-O. PMID 1639416.
6. "Entrez Gene: PTPN6 protein tyrosine phosphatase, non-receptor type 6".
7. Amin S, Kumar A, Nilchi L, Wright K, Kozlowski M (August 2011). "Breast cancer cells proliferation is regulated by tyrosine phosphatase SHP1 through c-jun N-terminal kinase and cooperative induction of RFX-1 and AP-4 transcription factors". Mol. Cancer Res. 9 (8): 1112–25. doi:10.1158/1541-7786.MCR-11-0097. PMID 21719561.
8. Liedtke M, Pandey P, Kumar S, Kharbanda S, Kufe D (October 1998). "Regulation of Bcr-Abl-induced SAP kinase activity and transformation by the SHPTP1 protein tyrosine phosphatase". Oncogene. 17 (15): 1889–92. doi:10.1038/sj.onc.1202117. PMID 9788431.
9. Kozlowski M, Larose L, Lee F, Le DM, Rottapel R, Siminovitch KA (April 1998). "SHP-1 binds and negatively modulates the c-Kit receptor by interaction with tyrosine 569 in the c-Kit juxtamembrane domain". Mol. Cell. Biol. 18 (4): 2089–99. doi:10.1128/mcb.18.4.2089. PMC 121439. PMID 9528781.
10. Yi T, Ihle JN (June 1993). "Association of hematopoietic cell phosphatase with c-Kit after stimulation with c-Kit ligand". Mol. Cell. Biol. 13 (6): 3350–8. doi:10.1128/mcb.13.6.3350. PMC 359793. PMID 7684496.
11. Blasioli J, Paust S, Thomas ML (January 1999). "Definition of the sites of interaction between the protein tyrosine phosphatase SHP-1 and CD22". J. Biol. Chem. 274 (4): 2303–7. doi:10.1074/jbc.274.4.2303. PMID 9890995.
12. Otipoby KL, Draves KE, Clark EA (November 2001). "CD22 regulates B cell receptor-mediated signals via two domains that independently recruit Grb2 and SHP-1". J. Biol. Chem. 276 (47): 44315–22. doi:10.1074/jbc.M105446200. PMID 11551923.
13. Greer SF, Justement LB (May 1999). "CD45 regulates tyrosine phosphorylation of CD22 and its association with the protein tyrosine phosphatase SHP-1". J. Immunol. 162 (9): 5278–86. PMID 10228003.
14. Law CL, Sidorenko SP, Chandran KA, Zhao Z, Shen SH, Fischer EH, Clark EA (February 1996). "CD22 associates with protein tyrosine phosphatase 1C, Syk, and phospholipase C-gamma(1) upon B cell activation". J. Exp. Med. 183 (2): 547–60. doi:10.1084/jem.183.2.547. PMC 2192439. PMID 8627166.
15. Adachi T, Wienands J, Wakabayashi C, Yakura H, Reth M, Tsubata T (July 2001). "SHP-1 requires inhibitory co-receptors to down-modulate B cell antigen receptor-mediated phosphorylation of cellular substrates". J. Biol. Chem. 276 (28): 26648–55. doi:10.1074/jbc.M100997200. PMID 11356834.
16. Pumphrey NJ, Taylor V, Freeman S, Douglas MR, Bradfield PF, Young SP, Lord JM, Wakelam MJ, Bird IN, Salmon M, Buckley CD (April 1999). "Differential association of cytoplasmic signalling molecules SHP-1, SHP-2, SHIP and phospholipase C-gamma1 with PECAM-1/CD31". FEBS Lett. 450 (1–2): 77–83. doi:10.1016/s0014-5793(99)00446-9. PMID 10350061.
17. Hua CT, Gamble JR, Vadas MA, Jackson DE (October 1998). "Recruitment and activation of SHP-1 protein-tyrosine phosphatase by human platelet endothelial cell adhesion molecule-1 (PECAM-1). Identification of immunoreceptor tyrosine-based inhibitory motif-like binding motifs and substrates". J. Biol. Chem. 273 (43): 28332–40. doi:10.1074/jbc.273.43.28332. PMID 9774457.
18. Keilhack H, Hellman U, van Hengel J, van Roy F, Godovac-Zimmermann J, Böhmer FD (August 2000). "The protein-tyrosine phosphatase SHP-1 binds to and dephosphorylates p120 catenin". J. Biol. Chem. 275 (34): 26376–84. doi:10.1074/jbc.M001315200. PMID 10835420.
19. Tomic S, Greiser U, Lammers R, Kharitonenkov A, Imyanitov E, Ullrich A, Böhmer FD (September 1995). "Association of SH2 domain protein tyrosine phosphatases with the epidermal growth factor receptor in human tumor cells. Phosphatidic acid activates receptor dephosphorylation by PTP1C". J. Biol. Chem. 270 (36): 21277–84. doi:10.1074/jbc.270.36.21277. PMID 7673163.
20. Keilhack H, Tenev T, Nyakatura E, Godovac-Zimmermann J, Nielsen L, Seedorf K, Böhmer FD (September 1998). "Phosphotyrosine 1173 mediates binding of the protein-tyrosine phosphatase SHP-1 to the epidermal growth factor receptor and attenuation of receptor signaling". J. Biol. Chem. 273 (38): 24839–46. doi:10.1074/jbc.273.38.24839. PMID 9733788.
21. Klingmüller U, Lorenz U, Cantley LC, Neel BG, Lodish HF (March 1995). "Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals". Cell. 80 (5): 729–38. doi:10.1016/0092-8674(95)90351-8. PMID 7889566.
22. Xu MJ, Zhao R, Cao H, Zhao ZJ (May 2002). "SPAP2, an Ig family receptor containing both ITIMs and ITAMs". Biochem. Biophys. Res. Commun. 293 (3): 1037–46. doi:10.1016/S0006-291X(02)00332-7. PMID 12051764.
23. Ganju RK, Brubaker SA, Chernock RD, Avraham S, Groopman JE (June 2000). "Beta-chemokine receptor CCR5 signals through SHP1, SHP2, and Syk". J. Biol. Chem. 275 (23): 17263–8. doi:10.1074/jbc.M000689200. PMID 10747947.
24. Kon-Kozlowski M, Pani G, Pawson T, Siminovitch KA (February 1996). "The tyrosine phosphatase PTP1C associates with Vav, Grb2, and mSos1 in hematopoietic cells". J. Biol. Chem. 271 (7): 3856–62. doi:10.1074/jbc.271.7.3856. PMID 8632004.
25. Saci A, Liu WQ, Vidal M, Garbay C, Rendu F, Bachelot-Loza C (May 2002). "Differential effect of the inhibition of Grb2-SH3 interactions in platelet activation induced by thrombin and by Fc receptor engagement". Biochem. J. 363 (Pt 3): 717–25. doi:10.1042/0264-6021:3630717. PMC 1222524. PMID 11964172.
26. Eklund EA, Goldenberg I, Lu Y, Andrejic J, Kakar R (September 2002). "SHP1 protein-tyrosine phosphatase regulates HoxA10 DNA binding and transcriptional repression activity in undifferentiated myeloid cells". J. Biol. Chem. 277 (39): 36878–88. doi:10.1074/jbc.M203917200. PMID 12145285.
27. Jiao H, Berrada K, Yang W, Tabrizi M, Platanias LC, Yi T (December 1996). "Direct association with and dephosphorylation of Jak2 kinase by the SH2-domain-containing protein tyrosine phosphatase SHP-1". Mol. Cell. Biol. 16 (12): 6985–92. doi:10.1128/mcb.16.12.6985. PMC 231702. PMID 8943354.
28. Wu DW, Stark KC, Dunnington D, Dillon SB, Yi T, Jones C, Pelus LM (February 2000). "SH2-Containing protein tyrosine phosphatase-1 (SHP-1) association with Jak2 in UT-7/Epo cells". Blood Cells Mol. Dis. 26 (1): 15–24. doi:10.1006/bcmd.2000.0273. PMID 10772872.
29. Mousseau DD, Banville D, L'Abbé D, Bouchard P, Shen SH (February 2000). "PILRalpha, a novel immunoreceptor tyrosine-based inhibitory motif-bearing protein, recruits SHP-1 upon tyrosine phosphorylation and is paired with the truncated counterpart PILRbeta". J. Biol. Chem. 275 (6): 4467–74. doi:10.1074/jbc.275.6.4467. PMID 10660620.
30. Sathish JG, Johnson KG, Fuller KJ, LeRoy FG, Meyaard L, Sims MJ, Matthews RJ (February 2001). "Constitutive association of SHP-1 with leukocyte-associated Ig-like receptor-1 in human T cells". J. Immunol. 166 (3): 1763–70. doi:10.4049/jimmunol.166.3.1763. PMID 11160222.
31. Fournier N, Chalus L, Durand I, Garcia E, Pin JJ, Churakova T, Patel S, Zlot C, Gorman D, Zurawski S, Abrams J, Bates EE, Garrone P (August 2000). "FDF03, a novel inhibitory receptor of the immunoglobulin superfamily, is expressed by human dendritic and myeloid cells". J. Immunol. 165 (3): 1197–209. doi:10.4049/jimmunol.165.3.1197. PMID 10903717.
32. Meyaard L, Adema GJ, Chang C, Woollatt E, Sutherland GR, Lanier LL, Phillips JH (August 1997). "LAIR-1, a novel inhibitory receptor expressed on human mononuclear leukocytes". Immunity. 7 (2): 283–90. doi:10.1016/s1074-7613(00)80530-0. PMID 9285412.
33. Xu Mj, Zhao R, Zhao ZJ (June 2000). "Identification and characterization of leukocyte-associated Ig-like receptor-1 as a major anchor protein of tyrosine phosphatase SHP-1 in hematopoietic cells". J. Biol. Chem. 275 (23): 17440–6. doi:10.1074/jbc.M001313200. PMID 10764762.
34. Fanger NA, Cosman D, Peterson L, Braddy SC, Maliszewski CR, Borges L (November 1998). "The MHC class I binding proteins LIR-1 and LIR-2 inhibit Fc receptor-mediated signaling in monocytes". Eur. J. Immunol. 28 (11): 3423–34. doi:10.1002/(SICI)1521-4141(199811)28:11<3423::AID-IMMU3423>3.0.CO;2-2. PMID 9842885.
35. Colonna M, Samaridis J, Cella M, Angman L, Allen RL, O'Callaghan CA, Dunbar R, Ogg GS, Cerundolo V, Rolink A (April 1998). "Human myelomonocytic cells express an inhibitory receptor for classical and nonclassical MHC class I molecules". J. Immunol. 160 (7): 3096–100. PMID 9531263.
36. Wang LL, Blasioli J, Plas DR, Thomas ML, Yokoyama WM (February 1999). "Specificity of the SH2 domains of SHP-1 in the interaction with the immunoreceptor tyrosine-based inhibitory motif-bearing receptor gp49B". J. Immunol. 162 (3): 1318–23. PMID 9973385.
37. Yu CL, Jin YJ, Burakoff SJ (January 2000). "Cytosolic tyrosine dephosphorylation of STAT5. Potential role of SHP-2 in STAT5 regulation". J. Biol. Chem. 275 (1): 599–604. doi:10.1074/jbc.275.1.599. PMID 10617656.
38. Chiang GG, Sefton BM (June 2001). "Specific dephosphorylation of the Lck tyrosine protein kinase at Tyr-394 by the SHP-1 protein-tyrosine phosphatase". J. Biol. Chem. 276 (25): 23173–8. doi:10.1074/jbc.M101219200. PMID 11294838.
39. Lorenz U, Ravichandran KS, Pei D, Walsh CT, Burakoff SJ, Neel BG (March 1994). "Lck-dependent tyrosyl phosphorylation of the phosphotyrosine phosphatase SH-PTP1 in murine T cells". Mol. Cell. Biol. 14 (3): 1824–34. doi:10.1128/mcb.14.3.1824. PMC 358540. PMID 8114715.
40. Binstadt BA, Billadeau DD, Jevremović D, Williams BL, Fang N, Yi T, Koretzky GA, Abraham RT, Leibson PJ (October 1998). "SLP-76 is a direct substrate of SHP-1 recruited to killer cell inhibitory receptors". J. Biol. Chem. 273 (42): 27518–23. doi:10.1074/jbc.273.42.27518. PMID 9765283.
41. Mizuno K, Katagiri T, Hasegawa K, Ogimoto M, Yakura H (August 1996). "Hematopoietic cell phosphatase, SHP-1, is constitutively associated with the SH2 domain-containing leukocyte protein, SLP-76, in B cells". J. Exp. Med. 184 (2): 457–63. doi:10.1084/jem.184.2.457. PMC 2192711. PMID 8760799.
42. Yoshida K, Kufe D (December 2001). "Negative regulation of the SHPTP1 protein tyrosine phosphatase by protein kinase C delta in response to DNA damage". Mol. Pharmacol. 60 (6): 1431–8. doi:10.1124/mol.60.6.1431. PMID 11723252.
43. Kumar S, Avraham S, Bharti A, Goyal J, Pandey P, Kharbanda S (October 1999). "Negative regulation of PYK2/related adhesion focal tyrosine kinase signal transduction by hematopoietic tyrosine phosphatase SHPTP1". J. Biol. Chem. 274 (43): 30657–63. doi:10.1074/jbc.274.43.30657. PMID 10521452.
44. Keilhack H, Müller M, Böhmer SA, Frank C, Weidner KM, Birchmeier W, Ligensa T, Berndt A, Kosmehl H, Günther B, Müller T, Birchmeier C, Böhmer FD (January 2001). "Negative regulation of Ros receptor tyrosine kinase signaling. An epithelial function of the SH2 domain protein tyrosine phosphatase SHP-1". J. Cell Biol. 152 (2): 325–34. doi:10.1083/jcb.152.2.325. PMC 2199605. PMID 11266449.
45. Yang J, Cheng Z, Niu T, Liang X, Zhao ZJ, Zhou GW (February 2000). "Structural basis for substrate specificity of protein-tyrosine phosphatase SHP-1". J. Biol. Chem. 275 (6): 4066–71. doi:10.1074/jbc.275.6.4066. PMID 10660565.
46. Dustin LB, Plas DR, Wong J, Hu YT, Soto C, Chan AC, Thomas ML (March 1999). "Expression of dominant-negative src-homology domain 2-containing protein tyrosine phosphatase-1 results in increased Syk tyrosine kinase activity and B cell activation". J. Immunol. 162 (5): 2717–24. PMID 10072516.
47. Yetter A, Uddin S, Krolewski JJ, Jiao H, Yi T, Platanias LC (August 1995). "Association of the interferon-dependent tyrosine kinase Tyk-2 with the hematopoietic cell phosphatase". J. Biol. Chem. 270 (31): 18179–82. doi:10.1074/jbc.270.31.18179. PMID 7629131.